This Research Career Award will support the development of Christopher R. McCartney, M.D., of the University of Virginia (UVa) as he continues to train in patient-oriented research under the mentorship of John C. Marshall, M.D., Ph.D., a renowned researcher in the fields of reproductive neuroendocrinology and the polycystic ovary syndrome (PCOS). This training will allow Dr. McCartney to acquire the knowledge and skills needed by an independent clinical researcher. To this end, the application outlines a career development plan that includes comprehensive instruction in clinical trials methodology, biostatistics, epidemiology, research ethics, assay methodology, and hormone pulse analysis; this will occur in part through the Master of Science Program in the UVa Dept. of Health Evaluation Sciences. Dr. McCartney's research proposal is designed to enhance understanding of the etiology of neuroendocrine abnormalities in PCOS, a very common but enigmatic disorder marked by hyperandrogenism, ovulatory dysfunction, and decreased fertility. Although the etiology of PCOS is unknown, relative gonadotropin-releasing hormone (GnRH) pulse generator resistance to negative feedback by progesterone (P) and estradiol (E2) contributes to a persistently rapid luteinizing hormone (LH) pulse frequency, ovulatory dysfunction, and hyperandrogenemia. GnRH pulse generator resistance to negative feedback may also be present in adolescents with hyperandrogenemia, felt to be a forerunner of adult PCOS; this would, in part, explain the pubertal genesis of abnormal LH secretion in adolescents destined to develop PCOS. The specific goals of this research are to delineate the relative roles of P and E2 in the regulation of the GnRH pulse generator throughout ovulatory menstrual cycles; to elucidate the potential role of P in directing diurnal changes of LH (and by inference GnRH) pulsatility in peripubertal adolescent girls; and to define abnormalities of gonadal steroid feedback on the GnRH pulse generator in hyperandrogenemic adolescents and in adults with PCOS. The research will be performed in a state-of-the-art General Clinical Research Center at UVa and, in conjunction with didactic training in scientific inquiry and data analysis, will permit Dr. McCartney's development into an independent patient-oriented investigator in the field of reproductive endocrinology. [unreadable] [unreadable]